Melamine & kidney damage

Melamine Nephrotoxicity: An Emerging Epidemic in an Era of Globalization: Global Impact of the Milk Contamination in China

Vivek Bhalla,1 Paul C. Grimm,2 Glenn M. Chertow,1 Alan C. Pao 1
Division of Nephrology, Department of Medicine, Stanford University, Stanford, California

Global Impact of the Milk Contamination in China
Melamine contamination of foodstuffs produced in China is an international public health crisis, and the full repercussions of this scandal may not be known for many years. A recent report by the World Health Organization (WHO) estimated that 51,900 children in the People's Republic of China have been affected and six deaths have resulted due to melamine contamination.[1] After initial reports of nephrolithiasis among Chinese infants who drank milk-based formula surfaced in the summer of 2008, a systematic search by the Chinese Administration of Quality Supervision, Inspection, and Quarantine (AQSIQ) revealed 22 commercial brands of milk powder (69 batches out of 491 tested) with detectable levels of melamine.[2] Thirteen of the batches contained > 2.5 parts per million (p.p.m.) (2.5 mg/kg), the level of melamine above which the United States Food and Drug Agency (USFDA) had conservatively concluded would exceed the tolerable daily intake of 0.063 mg/kg of body weight/day in humans.[3] The culprit powder with the highest melamine concentration, produced by the Shijiazhuang-based San Lu company, the largest national distributor and exporter of milk powder, contained samples with 2563 p.p.m. of melamine, more than 1000-fold higher than the USFDA tolerable daily intake.[2] As of 12 September 2008, 66 of 175 infant formula manufacturers across China had halted production, and the remaining 109 manufacturers were undergoing investigation. This controversy required reaction from the highest levels of the Chinese government. The chief of the AQSIQ, Li Changjang, resigned, and Premier Wen Jiabao recently apologized publicly and promised reform of current safety regulations.[4]

Children outside of mainland China in Taiwan, Hong Kong, and Macau have also been affected.[1] Reports of detectable melamine in foodstuffs from around the globe continue to document the widespread nature of this epidemic. Sixty-eight countries (see Figure 1) have already taken decisive action to limit the dissemination of contaminated products,[4] which include Chinese-made milk-based infant formula and milk-based products, such as cookies and chocolates (see Table 1). Other nations are now monitoring the incidence of nephrolithiasis as a surrogate for melamine intoxication in their respective populations.[5] Several international agencies including the World Health Organization (WHO), the Food and Agriculture Organization (FAO), the European Food Safety Association (EFSA), and the International Food Safety Authorities Network (INFOSAN) are working together to characterize and control this outbreak.[1] The USFDA has twice amended its assessment of melamine toxicity for infants, and concluded that only foods with less than 1 p.p.m. of melamine are safe for infants.[3] The USFDA has also announced the establishment of an office in Beijing, China to oversee exports shipped to the United States.[3]

Additional Melamine Contamination in Animal Feed
Two international incidents in 2004 and 2007 showed that pet food containing a wheat gluten exported from China was responsible for kidney failure and death in domesticated cats and dogs in the United States and Europe.[3] Pet food scraps in the United States from the 2007 outbreak revealed similar levels of melamine as the infant formulas recently produced in China, ranging from 9.4 to 1952 p.p.m.[3] as well as another compound, cyanuric acid.[3] The 2004 pet food outbreak is presumed to have been due to melamine because autopsy reports from 2004 are comparable with those of animals that died in 2007. In October 2008, hundreds of raccoon dogs in China died from kidney failure after the ingestion of melamine-contaminated animal feed. Reports from Hong Kong and other nations state that chicken eggs and fish (fit for human consumption) recently imported from China contain melamine,[4] providing circumstantial evidence that the food supply is now contaminated and demonstrating that this epidemic is pervasive. The WHO has criticized the Chinese government for not effectively eliminating melamine from the animal feed supply despite a ban imposed in June 2007.[4] Milk-based products, animals, and animal by-products are all believed to be potential sources of melamine exposure for humans.

Environmental Exposures and Kidney Disease
This Chinese milk controversy and emerging cases of kidney disease in infants is another reminder of how nephrology and the environment are intertwined. Many environmental and/or occupational kidney diseases have been described since the industrial revolution of the nineteenth century. Various toxins have been associated with AKI, CKD, and ESRD, whereas others have caused non-renal complications in persons with pre-existing kidney disease. Similar to melamine nephrotoxicity, most of these diseases have a known etiologic agent and yet, despite years of national and international safety regulations, are still with us today.

As organs responsible for much of the body's waste management, with extensive exposure to blood-borne toxins, the kidneys often bear the burden of clearing the bloodstream of materials to which humans are parenterally or enterally exposed. The recent recognition of acute phosphate nephropathy following exposure to phosphate-containing bowel preparations is a good example of this vulnerability.[14]

Just as melamine has emerged in the past few months, in an era of free trade and globalization, new toxins will certainly surface, and tools designed to rapidly identify cases and their etiology will be necessary. The prospect of earlier detection of AKI with novel biomarkers has gained traction over the past several years. Newer biomarkers could facilitate diagnosis of AKI in hospitalized patients and may also identify potentially nephrotoxic pharmaceuticals or food additives in preclinical studies.[15]

Several CKDs have been ascribed to occupational or environmental exposures. Occupational kidney diseases, including chronic lead nephropathy, cadmium nephrotoxicity, and nephropathy due to other heavy metals or solvents, have been described for decades,[13] but lead, for example, is still encountered today as a progression factor for CKD.[16] Analgesic nephropathy is caused by well-recognized, over-the-counter 'toxins,' particularly in Europe and Australia.[17] Aristolochic acid, which has been used as a component of weight loss regimens and is probably the etiologic agent of endemic Balkan nephropathy,[18] is an example of a toxin that was used therapeutically and/or was present in the environment and caused kidney disease for many years before being identified as such.

Several other toxic exposures have affected patients with pre-existing kidney disease by virtue of poor solute clearance. Itai-itai byo or 'ouch-ouch' disease in post-World War II Japan caused by cadmium contamination of rice fields downstream of metal mining operations - caused Fanconi syndrome and osteomalacia in many individuals, but those with decreased glomerular filtration rate were among the most severely affected.[13] Infants with CKD whose organ systems are still developing may be most sensitive and therefore act as 'sentinel canaries' for the detection of environmental toxins, where the effects may be amplified compared with those effects in adults. In pediatric patients with CKD, aluminum binders were often prescribed at the same time as citrate-containing base supplements to treat metabolic acidosis in CKD. This combination markedly increased the absorption of aluminum by the gastrointestinal tract further aggravating the neurotoxic effects of aluminum in the developing brain.[19] It is an important lesson that this interaction had been recognized in the early 1980s, but these therapies continued to be used by physicians for many years after. More recent concerns have centered on the use of gadolinium-chelating agents for contrast enhancement on magnetic resonance imaging. While epidemiologists eventually identified gadolinium as the culprit etiologic agent of nephrogenic systemic fibrosis, the insidious onset and relatively low incidence rate delayed recognition of the association for many years.[20]

These examples highlight the challenges facing nephrologists and other health providers in establishing links between hazardous environmental exposures, the development or progression of kidney disease, and/or complications of CKD. Particularly in view of the high prevalence of CKD, with a large fraction of the disease burden unexplained by known risk factors, we should probably adopt a high index of suspicion for environmental and/or occupational exposures as potential contributing causes.

for complete article:http://www.medscape.com/viewarticle/702630_6